U.S. Pat. No. 4,255,431 describes a compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridyl methyl sulfinyl]-(5-methoxy)-benzimidazole (Omeprazole) or pharmaceutically acceptable salt or non-toxic acid addition salt as a therapeutic compound for mammals including man, suffering from gastric acid secretion disturbances.
Omeprazole, however is only stable in basic pH conditions and degrades rapidly in neutral or acid pH environment. For this reason the omeprazole oral dosage form must be protected, not only from the acidic inert ingredients used to make a dosage form but also from the acidic gastric fluid in order to intactly reach the absorption site in the small intestine.
A study [Drug Dev. Ind. Pharm. 21(8), 965 (1995)] showed the effect of pH on the stability of omeprazole solution. The pH-decomposition rate profile curve indicated that the maximum stability was at pH 11. Below pH 7.8 the decomposition was very fast.
A survey of the stability of Omeprazole products from 13 countries was reported [Drug Dev. Ind. Pharm. 22(12), 1173(1996)]. The results of this independent survey of the stability of omeprazole solid dosage forms (20 mg) show that product available in many countries worldwide exhibits a very wide range of stability characteristics. Only 18% of very wide range of stability characteristics. Only 18% of total products tested (34) were considered to demonstrate good physical and chemical stability over the course of the study.
U.S. Pat. No. 4,628,098 discloses that: Lansoprazole is a substituted benzimidazole 2-[[[3-methyl-4-(2,2,2-trifluroethoxy)-2-pyridyl]methyl]sulfinyl] benzimidazole, a compound and a pharmacologically acceptable salt thereof that inhibits gastric acid secretion.
Lansoprazole is relatively stable when exposed to light. The compound degrades in aqueous solution, the rate of degradation increasing with decreasing pH.
It is well known in the pharmaceutical industry that an enteric coating technology is the most efficient means to protect acid unstable medication from the attack of the gastric fluid and can rapidly release the active drug in the proximal part of the gastrointestinal canal.
An enteric coated dosage form of omeprazole was reported in 1985 by Pilbrant and Cederberg (Scand. J. Gastroenterology 1985; 20 (supp.108) p. 113–120). It was found later that the stability of this dosage form was not sufficient for a long term commercial purpose.
Because of the acidic property of the enteric coating polymer, the omeprazole or lansoprazole will degrade and diminish its therapeutic value by direct or indirect contact with it during or after the coating process, even in the presence of alkaline inert ingredients with the active drug in the core particles. enteric coating as the second layer to release the active drug in the colon.
WO number 85/03436 describes a technique to mix active drug with buffering components (i.e. sodium dihydrogen phosphate) to maintain a constant pH in a core for particular purposes. The core is coated with a layer which controls the diffusions.
All of these inventions when applied to omeprazole's or lansoprazole's case will not give either an adequate release of active drug or storage stability of such dosage form.
U.S. Pat. No. 4,786,505 teaches an art to make an oral pharmaceutical preparation comprising (1) a core consisting of omeprazole plus an alkaline reacting compound (2) an inert subcoating of core (3) an enteric coating of subcoated core and to use it in the treatment of gastrointestinal disease.
This technique requires a series of cumbersome and laborious pharmaceutical processes: 1) preparation of the core, which should be suitable for multilayer coating 2) Coating the core with one or more layers of an inert subcoating containing one or more alkaline substances 3) applying an outer enteric coating to the subcoated core 4) make the pharmaceutical preparation for therapeutical use.
U.S. Pat. No. 5,232,706 claims an oral pharmaceutical preparation of omeprazole or an alkali salt of omeprazole and a process for producing such preparation. The design principle of the preparation is basically similar to the U.S. Pat. No. 4,786,505. This preparation is comprised of: 1) a nucleus of active drug and first basic organic compound; 2) a first coating of nucleus containing at least a layer of a basic water soluble excipient and a second basic organic compound; and 3) a second coating formed by an enteric coating.
The major difference between U.S. Pat. No. 5,232,706 and U.S. Pat. No. 4,786,505 is the type of basic compound used; the former uses basic organic compound the later uses inorganic alkaline reaction compounds in core and in subcoating.
U.S. Pat. No. 5,385,739 relates to a stable formulation of Omeprazole microgranules containing a neutral core of sugar and starch coated with an active layer of drug and mannitol powder mixture with the aid of a solution of a binding agent in water plus ethanol. An additional protective layer of mannitol and sugar syrup is then applied prior to the final gastroprotection coating.
The art of coating a powder mixture containing an active ingredient onto the core of sugar and starch by using a binding solution is a rather difficult process to obtain uniform drug core granules.
In addition, two applications of aqueous solution involving the direct contact with Omeprazole, in the coating process, may effect the stability of this moisture-sensitive drug.
U.S. Pat. No. 5,399,700 teaches a method for stabilizing an acid unstable benzimidazole derivative, by forming an inclusion complex of Omeprazole with cyclodextrin.
This inclusion complex was synthesized in an aqueous alkaline solution at 40°–70° C. and then used to manufacture a tablet which is first coated by a water soluble substance and then with an enteric substance to form an enteric coated oral drug.
The safety of cyclodexrin for human oral dosage form needs to be clarified. Even if the acid stability and dissolution characterization of this inclusion complex has been well demonstrated in vitro, its behavior in vivo is not referenced in this patent.
U.S. Pat. No. 4,689,333 claims a pharmaceutical composition for preventing or treating digestive ulcers or gastritis which contains an effective amount of Lansoprazole or a pharmacologically acceptable salt thereof and pharmacologically acceptable carriers.
A study [Drug Dev. Ind. pharm. 18 (13), 1437 (1992)] reported that enteric granule formulations for Lansoprazole was established, however, it was difficult because some of the excipients needed for these formulations are incompatible with the drug. The alkaline stabilizers were then screened and the optimal pH stability of 9 was suggested in this paper.
A continued study from the above mentioned effort [Drug Dev. Ind. pharm. 20(9), 1661 (1994)] attempted to prepare more stable enteric granules without using these troublesome excipients by using a centrifugal fluid-bed granulator instead of an extruder-spheronizer. It was said that with this method more stable enteric granules could be obtained. The utilization of special sophisticated equipment to achieve the stable granules may suffer economical disadvantages.
U.S. Pat. No. 5,026,560 discloses spherical granules having a seed core coated with a binder and spraying powder containing lansoprazole as active drug, low substituted hydroxypropylcellulose and magnesium or calcium carbonate as alkaline agents. The powder coated core is further coated with spraying powder of low substituted hydroxypropylcellulose and then with enteric coating agent.
Technically, powder coating in pharmaceutical manufacturing brings forth issues such as content uniformity of the active on the seed core, laborious process attention and time consumption. It therefore tremendously increases the cost of the product.
U.S. Pat. No. 5,045,321 describes a pharmaceutical composition for coated tablets or granules, which is comprised of lansoprazole being in contact with at least one of the basic inorganic salts evenly. No protective and/or enteric coating is mentioned in the patent claim.
U.S. Pat. No. 5,093,132 is similar to the U.S. Pat. No. 5,045,321 but more specifically, describes an oral stabilized pharmaceutical composition for the inhibition of gastric acid secretion comprising of lansoprazole or its pharmaceutically acceptable salt in contact evenly with a basic inorganic salt stabilizing agent. It also mentions simply an enteric coating for the composition.
Enteric coated oral solid dosage forms have been in existence for a century. U.S. Pat. Nos. 3,656,997 and 3,959,540 disclosed a coated gastric juic resistant capsules and process for the production thereof. Most commercially available products under this category are coated pellets or granule filled capsules and tablet dosage forms. The concept of an enteric coated capsule dosage for commercial purposes are relatively new. So far, only one prescription product—VIVOTIF BERNA™ (Berna Products, Co., Coral Gables, Fla.) is in the U.S.A. market.
The advantage of enteric coated capsules are duplex. In addition to the merit natures of enteric coating polymers, the problem involved and the need for extensive efforts in development and the preparation of enteric pellets or tablets can be avoided.
Historically, enteric coated hard shell capsules were manufactured with formaldehyde treatments. This technology results in a stability problem with this product. Since the successful introduction of a number of enteric polymeric materials, the technology of this coating becomes more popular and is increasingly used in the pharmaceutical industry. However, the use of organic solvents causes risks of air pollution and inflammability. With the advent and availability of aqueous enteric polymer dispersions, manufacturing of enteric coated dosage forms have acquired a great deal of attention. The modern coating equipment now offers to pharmaceutical manufacturers better conditions for the application of aqueous coatings.
The process of enteric coating for pharmaceutical dosage forms are not significantly different with other coating processes. Generally, the sample is first placed in the coating pan or in the fluid-bed chamber for fluidization, while a coating solution is then spraying through a gun according to the two operations: 1) spraying or wetting and 2) drying, which is repeated consecutively during the process.